6, 16-dihalo-17-acyloxy-progesterones



United States Patent Ofifice 3,067,213 Patented Dec. 4, 1962 3,067,2136,16-DIHALO-17-ACYLOXY-PROGESTERONES Howard J. Ringold and CarlDjerassi, Mexico City, Mexico, assignors, by mesne assignments, toSyntex Corporation, a corporation of Panama No Drawing. Filed May 13,1959, Ser. No. 812,829 Claims priority, application Mexico May 15, 19583 Claims. (Cl. 260-397.4)

The present invention relates to novel cyclopentanophenanthrenecompounds.

More particularly, it relates to the novel 16/3-halo (chloro or=bromo)-17a-acyloxy-progesterones which may further possess a fluorine,chlorine or methyl substituent at C-6u.

We have found that these compounds exhibit progestational activity and,furthermore, possess anti-androgenic and anti-estrogenic effects.

The novel compounds having the properties above set forth areillustrated by the following formula:

n on? CH5 CH3 0 o I OH I -o R1 or oit it In the above equation X, R andR represent the same groups as heretofore.

For the preparation of the novel compounds of the invention, weesterified the hydroxyl group of a 16fi-halo- 17a-hydroxy-progesteroneor of its analogs further substituted at C-6 x (I), with radicals ofhydrocarbon carboxylic acids having up to 12 carbon atoms, and thus weproduced the desired 16B-halo-17a-acyloxy-progesterones (II; R=H), ortheir analogs further substituted at C-6u (II; R=F, Cl or Me),respectively. This esterification was achieved by reaction with theanhydride of the corresponding carboxylic acid in a solvent inert tothis reaction such as benzene or ethyl acetate in the presence of anacid catalyst preferably p-toluenesulfonic acid at room temperature.

Of the starting compounds there have been already described16fi-bromo-17a-hydroXy-pr0gesterone (Romo et al. J. Org. Chem. 21, 902(1956)). We obtained 16schloro-17u-hydroxy-progesterone by following themethod described by Romo et al. (loc. cit.) for the preparation of the16/8-bromo-analog, that is, by treatment of 16a,17aoxido-progesteronewith hydrochloric acid. The method employed for preparing the so farunknown 16B-chloro and l6 8-b'romo analogs of6oc-methyl-l7a-hydroxyprogesterone, is represented by the followingequation:

@15 a wig to l a a r g. w

In the above equation X represents the same groups as heretofore.

We started from the known 6a-methyl-17a-hydroxyprogesterone, US. patentapplication Serial No. 679,763, filed August 22, 1957, which wasconverted into its 3,20- bis-cycloethyleneketal (III); the latter wasdehydrated and the ketal groups were then hydrolyzed toproducecamethyl-A -pregnadien-3,20-dione (IV), whose double bond between0-16 and C-17 was epoxidized to produce the compound of Formula V, whichwas in turn converted into the halohydrin VI.

The following specific examples serve to illustrate but are not intendedto limit the present invention.

Example I solution of permonophthalic acid containing 1.2 molareqivalents of the peracid and the mixture was kept standing at roomtemperature for 20 hours. It was then diluted with water and the organiclayer was separated, washed with water, aqueous sodium bicarbonatesolution and finally again with water, dried over-anhydrous sodiumsulfate and evaporated to dryness. The residue consisted of a mixture of5a,6a;16a,17a-bis-0xido-A -pregnen- 3fl-ol-20-one and of5fi,6{3;16a,17a-bis-oXido-A -pregnen- 3B-ol-20-one. The50:,6oc-1SOI1'16I' was separated by chromatography on neutral alumina.

A solution of 3 g. of the above compound in 300 cc. of a mixture ofequal parts of ether and benzene was treated with 3 cc. of borontrifluoride etherate and the mixture was kept at room temperature for 3hours and then washed with water, dried over anhydrous sodium sulfateand evaporated to dryness. The residue was purified by chromatography onneutral alumina, to give 65-fiuoro-l6a,17a-oxido-pregr1an-3[3,Sa-diol-20-one.

A solution of 3 g. of the above compound in 150 cc. of acetone wascooled to C. and treated with an 8 N solution of chromic acid preparedfrom 1.6 g. of chromium trioxide, concentrated sulfuric acid and water;the addition was effected in the course of 2 minutes, with stirring andmaintaining the temperature at around 0 C., under an atmosphere ofnitrogen. The mixture was stirred for minutes longer under an atmosphereof nitrogen and then it was diluted with water and extracted with ether;the extract was washed with water, dried over anhydrous sodium sulfateand evaporated to dryness. The residue crystallized from ether-hexane,thus yielding 6fl-fl'uoro- 16a,17a-0xido-pregnan-5a-ol-3,20-dione.

A mixture of 2 g. of the above compound and 100 cc. of glacial aceticacid was treated with a slow stream of dry hydrogen chloride for 2hours, maintaining the temperature at around C. The mixture was pouredinto water and the precipitate formed was collected, washed with water,dried and recrystallized from acetone-hexane. There was thus obtained6a-fiuoro-16fl-chloro-A -pregnen- 17oc-Ol-3,20-(li0[l6.

Example II A mixture of 5 g. of 16a,17a-oxido-A -pregnen-3,2O- dione, 50cc. of anhydrous dioxane, 5 cc. of ethyl orthoformate and 150 mg. ofp-tolucnesul fonic acid was stirred for one and a half hours and then 4cc. of pyridine and 100 cc. of water were added. The mixture was cooledand the precipitate was collected, washed with water, dried andrecrystallized from aqueous methanol. There was thus obtained3-ethoxy-16a,l7a-oxido-A -pregnadien- -one.

A mixture of 5 g. of the above enol-ether, 2 g. of anhydrous sodiumacetate and 100 cc. of acetone was treated with 32 cc. of water and thesolution was cooled to a temperature between 0 and 5 C. There were thenadded 4 g. of N-chlorosuccinimide and 2 cc. of glacial acetic acid andthe mixture was stirred at 05 C. for 60 minutes and diluted with 300 cc.of Water. After keeping the mixture overnight in the refrigerator, theprecipitate was collected, washed with water, dried in vacuo andrecrystallized from acetone. There was thus obtained 6/8- chloro-I 60c,l7a-oxido-progesterone.

A slow stream of dry hydrogen chloride was introduced for one hour intoa mixture of 2 g. of 6p-chloro-16a,17ooxido-progesterone, and 100 cc. ofglacial acetic acid, maintaining the temperature at around 15 C. It wasthen poured into water, the precipitate was collected, washed withwater, dried and recrystallized from acetonehexane, thus affording6a,16fi-dichloro-A -pregnen-l7a-ol- 3,20-dione.

Example III 10 cc. of a saturated solution of dry hydrogen chloride inglacial acetic acid was added to a mixture of 10 g. ofl6a,l7u-oxido-progesterone and 80 cc. of glacial acetic acid, withstirring and maintaining the temperature below 20 C. After minutesstanding at room temperature, the mixture was poured into ice water andthe precipitate formed was collected by filtration, washed with water,dried and recrystallized from chloroformmethanol. There was thusobtained l6/8chloro-17a-l1ydroxy-progesterone.

Example IV A mixture of 8 g. of 6a-methyl-l7u-hydroxy-progesterone, 160cc. of anhydrous benzene, 56 cc. of ethyleneglycol distilled over sodiumhydroxide and 0.9 g. of p-toluenesulfonic acid was refluxed for 8 hourswith the use of an adapter for the removal of the water formed duringthe reaction. The cooled mixture was treated with aqueous sodiumbicarbonate solution and the organic layer was separated, washed withwater, dried over anhydrous sodium sulfate and evaporated to dryness.Crystallization of the residue from acetone-hexane yielded 6-methyl-3,2O-bis-ethylenedioxy-A -pregnen-17a-o1. Q

A solution of 6 g. of the above compound in cc. of pyridine was cooledto 0 C. and slowly treated under stirring with 3.2 cc. of thionylchloride, while the ternperature was maintained at around 0 C. Themixture was kept at 0 C. for 12 hours and then poured into ice water;the precipitate was collected, washed with water, dried and used for thesubsequent step without further purification.

The above crude product was dissolved in 120 cc. of acetone, mixed with10 cc. of water and 600 mg. of p-to1uenesul fonic acid and stirred at 15C. for 24 hours. The mixture was poured into ice water and theprecipitate was collected, washed with Water, dried and recrystallizedfrom acetone-hexane. There was thus obtained Got-methyl-A-pregnadien-3,20-dione.

To a solution of 5 g. of the above compound in cc. of ethyl acetatethere was added 80 cc. of a solution of perbenzoic acid in ethyl acetatecontaining 29 mg. of the reagent per cc. The mixture was kept in thedark at room temperature for 19 hours and then diluted with more ethylacetate; the solution was washed with aqueous 5% sodium carbonatesolution and then with 10% sodium chloride solution until neutral; theorganic layer was dried over anhydrous sodium sulfate and evaporated todryness under reduced pressure. The residue crystallized fromacetone-hexane to furnish 6a-methyl-16a,l7a-oxido-pro gesterone.

A solution of 3 g. of the above compound in 30 cc. of glacial aceticacid was treated with 3 cc. of a saturated solution of dry hydrogenchloride in glacial acetic acid, as described in Example III. Theproduct was precipitated by the addition of water, filtered andrecrystallized from chloroform-methanol, thus producing6a-rnethyl-l6fichloro-17a-hydroxy-progesterone.

Example V By substituting in the method of the previous example, thehydrogen chloride for hydrogen bromide, there was obtained6a-methyl16/8-bromo-l7u-hydroxy-progesterone.

Example VI A solution of 5 g. of l6,6-chloro-l7u-hydroxy-proges teronein 500 cc. of dry benzene was mixed with 10 cc. of acetic anhydride andl g. of p-toluenesulfonic acid and the mixture was kept at roomtemperature for 24 hours. The benzene solution was washed with aqueoussodium bicarbonate solution and then with Water to neutral, dried overanhydrous sodium sulfate and evaporated to dryness. The residue waspurified by chromatography on neutral alumina, thus yielding16fi-chlOr0-l7a-hYdroXY- progesterone 17-acetate.

Example VII By the same method of the previous example16flbromo-l7a-hydroxy-progesterone was acetylated at C17.

Example VIII In the method of Example VI there was substituted theacetic anhydride for 20 cc. of caproic anhydride and the mixture wasallowed to react for 4 days. The product was isolated by following thetechnique described in such example, thus producing16B-chlcro-l7a-hydroxy-progesterone 17-caproate.

Example IX The methods of the previous examples were applied to all ofthe l6fi-halo (chloro or bromo)-l7a-hydroxy-progesterones substituted at0-60; with fluorine, chlorine or methyl, and/or there were used otheracid anhydrides of hydrocarbon carboxylic acids of up to 12 carbonatoms. There were thus prepared a great variety of 17-esters of thel6/3-chloro and 16/3-bromo analogs of 17a-hydroxyprogesterone, with orwithout the additional fluorine, chlorine or methyl substituent at C6,including in addition to the acetates, propionates and caproates, thebenzoates and eyclopentylpropionates.

We claim:

1. The hydrocarbon carboxylic esters of up to 12 carbon atoms of6a,16B-dichloro-17u-hydroxyprogesterone.

2. The hydrocarbon carboxylic esters of up to 12 carbon atoms of6a-fluoro-16,8-ch1oro-17m-hydroxyprogesterone.

3. The hydrocarbon carboxylic esters of up to 12 carbon atoms of6a-methy1-16p-ch1oro-17a-hydroxyproges- 10 terone.

References Cited in the file of this patent UNITED STATES PATENTS Kasparet a1. July 3, 1956 Miramontes et a1 Mar. 17, 1959 Romo et al.: J. Org.Chem., 21, pp. 902; 903-907 (1956).

1. THE HYDROCARBON CARBOXYLIC ESTERS OF UP TO 12 CARBON ATOMS OF6A,16B-DICHLORO-17A-HYDROXYPROGESTERONE.